Activated Notch1 interacts with p53 to inhibit its phosphorylation and transactivation
Activated Notch1 interacts with p53 to inhibit its phosphorylation and transactivation
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DOI：
10.1038/sj.cdd.4402083
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发表时间：
2007-05-01
影响因子：
12.4
通讯作者：
Joe, C. O.
中科院分区：
文献类型：
--
作者：
Kim, S. B.;Chae, G. W.;Joe, C. O.
我们提出了 Notch 信号传导对 p53 反式激活功能的负面作用的生化机制。人Notch1 (Notch1-IC) 胞内结构域的表达抑制HCT116 p53(-/-) 细胞中p53 响应基因p21、mdm2 和bax 的表达。此外，Notch1-IC 的表达抑制 HCT116 p53(-/-) 细胞中异位表达的 p53 的磷酸化，以及紫外线处理的 HCT116 p53(+)/(+) 细胞中内源性 p53 的磷酸化。通过染色质免疫沉淀测定和 Northern 印迹分析证实了 Notch1-IC 对 p53 反应基因的转录下调。我们在 HCT116 p53(+/+) 细胞中发现了 Notch1-IC 和 p53 之间的细胞内相互作用，并表明激活的 Notch1 与 p53 的相互作用是抑制 p53 依赖性反式激活的重要细胞事件。 Notch1-IC 的 N 端片段可以与 p53 相互作用，抑制 p53 磷酸化并抑制 p53 反式激活。此外，Notch 信号传导下调了紫外线照射诱导的 p53 依赖性细胞凋亡。
We propose a biochemical mechanism for the negative role of Notch signaling on p53 transactivation function. Expression of the intracellular domain of human Notch1 (Notch1- IC) inhibits the expression of p53-responsive genes p21, mdm2, and bax in HCT116 p53(-/-) cells. Furthermore, Notch1-IC expression inhibits the phosphorylation of ectopically expressed p53 in HCT116 p53(-/ -) cells as well as the phosphorylation of endogenous p53 in UV-treated HCT116 p53(+)/(+) cells. Transcriptional downregulation of p53- responsive genes by Notch1-IC was confirmed both by chromatin immunoprecipitation assay and Northern blot analysis. We found the intracellular interaction between Notch1-IC and p53 in HCT116 p53(+/+) cells and suggest that activated Notch1 interaction with p53 is an important cellular event for the inhibition of p53-dependent transactivation. The N-terminal fragment of Notch1-IC, which can interacts with p53, inhibits p53 phosphorylation and represses p53 transactivation. In addition, Notch signaling downregulated p53-dependent apoptosis induced by UV irradiation.